Development of a new trategy for low HDL in homogygous FH patients

• Project/Area Number: 20K08439
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: National Defense Medical College
• Principal Investigator: Ikewaki Katsunori 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 内科学, 教授 (40287199)
• Co-Investigator(Kenkyū-buntansha): 小倉 正恒 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (30532486) ; 末永 由美子 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 内科学, 助教 (30815337) ; 佐々木 誠 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 内科学, 助教 (60837251)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: FH / HDL / apoA-I / apoA-II / stable isotope / catabolism / 家族性高コレステロール血症 / アポ蛋白A-I / アポ蛋白A-II / 安定同位体 / 異化速度 / 産生速度 / 安定同意体 / トレーサー / HDL機能

Outline of Research at the Start

安定同位体は、ヒトの体内での蛋白代謝動体を評価できる方法で、海外では放射活性物質で蛋白をラベルする方法が実施可能であるが、我が国ではできないため、この安定同位体方が唯一の実験手段である。家族性高コレステロール血症(FH)はLDL高値が注目されているが、こう動脈硬化性リポ蛋白であるHDLが低く、これがFHの心血管リスクをさらに高めることがわかっており、低HDL血症の病態解明が必要である。加えて、HDLは濃度(量)ではなく機能(質)が重要との認識が高まっており、FHにおいてHDLの質の異常の検討も重要である。本研究では、FHでの低HDL血症の病態をHDL機能を評価する。

Outline of Final Research Achievements

FH homozygote is considered to be very high risk for atherosclerosis. Low HDL-C contribute in part for the increased atherosclerosis risk. Therefore, we aimed to elucidate kinetic pathophysiology for low HDL. We performed in vivo kinetic studies using endogenously-labeled stable isotope in 7 FH homozygotes. Kinetic studies revealed that fractional catabolic rates of apoA-I and apoA-II, major constituents of HDL, were markedly increased by about 50% as compared with control subjects with relatively unchanged synthetic rates. Therefore, low HDL levels was primarily due to increased catabolism in FH homozygotes. These findings may imply that therapy such as CETP inhibitors can normalized increased catabolic rates, thereby normalizing HDL-C in FH homozygotes. This may be a novel therapeutic strategy for treatment-resistant homozygous FH patients.

Academic Significance and Societal Importance of the Research Achievements

FH homozygotes needs early and effective treatment. The present study discovered that increased catabolic rate caused low HDL-C, another additive atheroscleritic risk. Based on our findings, we may develop a new therapy to nomalize catbolism to reduce the risk in FH homozygotes.

Research Products

• [Journal Article] Two Cases of Acquired High-Density Lipoprotein Deficiency with Immunoglobulin G4-Related Lecithin–Cholesterol Acyltransferase Autoantibody (2023)
  • Author(s): Komatsu T , Katsurada Y, Miyashita K, Abe S, Nishida T, Endo Y, Teramoto M, Sasaki K, Arakawa J, Sasaki M, Suzuki N, Kuwata K, Imakiire T, Miyake T, Sakurada M, Matsukuma S|, Hirano T, Uehara Y, Ikewaki K
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 30 Issue: 8 Pages: 1070-1082
  • DOI: 10.5551/jat.63616
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2023-08-01
  • Peer Reviewed / Open Access
• [Journal Article] Intestinal Cholesterol Absorption in Diabetes Mellitus (2023)
  • Author(s): Endo Y, Fujita M, Ikewaki K
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 30 Issue: 7 Pages: 733-734
  • DOI: 10.5551/jat.ED220
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2023-07-01
  • Peer Reviewed / Open Access
• [Journal Article] HDL Functions-Current Status and Future Perspectives (2023)
  • Author(s): Endo Y, Fujita M, Ikewaki K
  • Journal Title: Biomolecules Volume: 13 Issue: 1 Pages: 105-120
  • DOI: 10.3390/biom13010105
  • Peer Reviewed / Open Access
• [Journal Article] Immune checkpoint inhibitor-related myositis and myocarditis with multiple myositis-specific/?associated antibodies (2023)
  • Author(s): Isa Megumi、Hongo Yu、Sakamoto Naohiro、Yamazaki Keishi、Takazaki Hiroshi、Asakuma Junichi、Ikewaki Katsunori、Suzuki Kazushi
  • Journal Title: Journal of the Neurological Sciences Volume: 444 Pages: 120528-120528
  • DOI: 10.1016/j.jns.2022.120528
  • Peer Reviewed
• [Journal Article] Effects of Dietary Education Program for the Japan Diet on Cholesterol Efflux Capacity: A Randomized Controlled Trial (2022)
  • Author(s): Umezawa A, Maruyama C, Endo T, Suenaga Y, Shijo Y, Kameyama N, Sato A, Nishitani A, Ayaori M, Waki M, Teramoto T, Ikewaki K
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 29 Issue: 6 Pages: 881-893
  • DOI: 10.5551/jat.62832
  • NAID: 130008041687
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2022-06-01
  • Peer Reviewed / Open Access
• [Journal Article] Atorvastatin Reduces Circulating S100A12 Levels in Patients with Carotid Atherosclerotic Plaques - A Link with Plaque Inflammation (2022)
  • Author(s): Komatsu T , Ayaori M, Uto-Kondo H, Hayashi K, Tamura K, Sato H, Sasaki M, Nishida T, Takiguchi S, Yakushiji E, Nakaya K, Ikewaki K
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 29 Issue: 5 Pages: 775-784
  • DOI: 10.5551/jat.61630
  • NAID: 130008032980
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2022-05-01
  • Peer Reviewed / Open Access
• [Journal Article] An Atypical Phenotype of Chronic Inflammatory Demyelinating Polyradiculoneuropathy Associated with Ocular Palsy, IgM-anti Ganglioside Antibody, and Fever-induced Recurrence (2022)
  • Author(s): Horiuchi Midori、Hongo Yu、Yamazaki Keishi、Komuta Yukari、Kadoya Masato、Takazaki Hiroshi、Furuya Yuichiro、Matsui Taro、Sakamoto Naohiro、Ikewaki Katsunori、Suzuki Kazushi、Kaida Kenichi
  • Journal Title: Internal Medicine Volume: 61 Issue: 8 Pages: 1247-1252
  • DOI: 10.2169/internalmedicine.7526-21
  • NAID: 130008101316
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2022-04-15
  • Peer Reviewed / Open Access
• [Journal Article] Clinically undetected plasmacytoid urothelial carcinoma of the urinary bladder with non-mass-forming metastases in multiple organs: an autopsy case (2022)
  • Author(s): Asano Y, Miyai K, Yoshimatsu S, Sasaki M, Ikewaki K, Matsukuma S
  • Journal Title: J. Pathol. Transl Med Volume: 56 Issue: 4 Pages: 217-224
  • DOI: 10.4132/jptm.2022.03.15
  • Peer Reviewed / Open Access
• [Journal Article] Effects of Nutrition Education Program for the Japan Diet on Serum LDL-Cholesterol Concentration in Patients with Dyslipidemia: A Randomized Controlled Trial (2021)
  • Author(s): Chizuko Maruyama, Yuri Shijo, Noriko Kameyama, Ariko Umezawa, Aisa Sato, Ai Nishitani, Makoto Ayaori, Katsunori Ikewaki, Masako Waki, Tamio Teramoto
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 28 Issue: 10 Pages: 1035-1051
  • DOI: 10.5551/jat.60376
  • NAID: 130008095586
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2021-10-01
  • Peer Reviewed / Open Access
• [Journal Article] Diagnosis and Management of Sitosterolemia 2021 (2021)
  • Author(s): Tada H, Nomura A, Ogura M, Ikewaki K, Ishigaki Y, Inagaki K, Tsukamoto K, Dobashi K, Nakamura K, Hori M, Matsuki K, Yamashita S, Yokoyama S, Kawashiri MA, Harada-Shiba M.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 28 Issue: 8 Pages: 791-801
  • DOI: 10.5551/jat.RV17052
  • NAID: 130008070338
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2021-08-01
  • Peer Reviewed / Open Access
• [Journal Article] Current Status of Familial LCAT Deficiency in Japan (2021)
  • Author(s): Kuroda Masayuki、Bujo Hideaki、Yokote Koutaro、Murano Takeyoshi、Yamaguchi Takashi、Ogura Masatsune、Ikewaki Katsunori、Koseki Masahiro、Takeuchi Yasuo、Nakatsuka Atsuko、Hori Mika、Matsuki Kota、Miida Takashi、Yokoyama Shinji、Wada Jun、Harada-Shiba Mariko.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 28 Issue: 7 Pages: 679-691
  • DOI: 10.5551/jat.RV17051
  • NAID: 130008060155
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2021-07-01
  • Peer Reviewed / Open Access
• [Journal Article] High-Density Lipoprotein Cholesterol Efflux Capacity as a Novel Prognostic Surrogate for Coronary Artery Disease (2021)
  • Author(s): Hisauchi I, Ishikawa T, Ayaori M, Uto-Kondo H, Koshikawa Y, Ukaji T, Nakamura H, Mizutani Y, Taguchi I, Nakajima T, Mutoh M, Ikewaki K.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 28 Issue: 7 Pages: 696-702
  • DOI: 10.5551/jat.59279
  • NAID: 130008060154
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2021-07-01
  • Peer Reviewed / Open Access
• [Journal Article] Increase of serum uric acid levels associated with APOE ε2 haplotype: a clinico-genetic investigation and in vivo approach (2021)
  • Author(s): Ogura Masatsune、Toyoda Yu、Sakiyama Masayuki、Kawamura Yusuke、Nakayama Akiyoshi、et al.
  • Journal Title: Human Cell Volume: 34 Issue: 6 Pages: 1727-1733
  • DOI: 10.1007/s13577-021-00609-w
  • Peer Reviewed / Open Access
• [Presentation] Establishment of acute hypergravity rat models (2023)
  • Author(s): Endo , Fujita M, Tandai-Hiruma M, Nakamura S, Ikewaki K
  • Organizer: American Physiol- ogy Summit 2023, American Physiology Society
  • Int'l Joint Research
• [Presentation] 睡眠時無呼吸症候群は HDL プロテオームを変化さ せる (2023)
  • Author(s): Endo Y, Sasaki M, Arakawa J, Suenaga Y, Nakayama H, Inoue Y, Fujita M, Ikewaki K
  • Organizer: 第87回日本循環器学会学術集会
• [Presentation] Association between oxidized lp(a) and HDL functions in sleep apnea syndrome (2022)
  • Author(s): Endo Y, Sasaki M, Teramoto M, Arakawa J, Suenaga Y, Ayaori M, Nakayama H, Inoue Y, Ikewaki K
  • Organizer: The 90th Congress of the European Atherosclerosis Society
  • Int'l Joint Research
• [Presentation] 睡眠時無呼吸症候群患者において低酸素環境はコレステロール引き抜き能を低下させる (2022)
  • Author(s): 遠藤康弘、佐々木誠、寺本麻菜美、荒川純子、末永由美子、綾織誠人、中山秀章、井上雄一、池脇克則
  • Organizer: 第54回日本動脈硬化学会総会・学術集会
• [Presentation] 労作時息切れを主訴とした高齢狭心症患者の１例 (2022)
  • Author(s): 小網礼恵、佐々木誠、寺本麻菜美、遠藤康弘、荒川純子、平本剛士、江崎裕敬、桜田真弓池脇克則
  • Organizer: 第74回日本老年医学会関東甲信越地方会
• [Presentation] 自律神経障害を呈するギ ランバレー症候群の臨床的 特徴と抗糖脂質抗体の解析 (2022)
  • Author(s): 高崎寛, 本郷悠, 山崎啓史, 松井太郎, 小牟田 縁, 桑原基, 楠進, 池脇克則, 海田賢一, 鈴木一詩
  • Organizer: 第75回日本自律神経学会総会
• [Presentation] Cholesterol 付加によ り変化する糖脂質抗体結合活 性の検証 (2022)
  • Author(s): 本郷悠, 髙﨑寛, 山﨑啓史, 小牟田縁, 池脇克則 , 鈴木一詩, 海田賢一
  • Organizer: 第 63 回 日本神経学会学 術集会
• [Presentation] コレステロール搬出反応(CEC)の冠動脈疾患予測因子としての意義－新規糖尿病関連マーカーを加えた解析から－ (2021)
  • Author(s): 佐々木誠、江崎裕敬、綾織誠人、政木隆博、越智小枝、三宅隆之、谷脇正哲、荒川純子、末永由美子、遠藤康弘、桜田真己、松浦知和、池脇克則
  • Organizer: 第53回日本動脈硬化学会総会・学術集会
• [Presentation] 睡眠時無呼吸症候群患者におけるコレステロール引き抜き能とoxLp(a)との関連性についての検討 (2021)
  • Author(s): 遠藤康弘、佐々木誠、寺本麻菜美、末永由美子、綾織誠人、中山秀章、井上雄一、池脇克則
  • Organizer: 第53回日本動脈硬化学会総会・学術集会
• [Presentation] 脂質異常症患者における食物摂取頻度と血中LDL-C濃度の関連（簡易式食物摂取頻度調査票を用いた検討） (2021)
  • Author(s): 梅澤愛理子、丸山千寿子、四條裕里、亀山詞子、佐藤愛紗、西谷藍、池脇克則、綾織誠人脇昌子、寺本民生
  • Organizer: 第53回日本動脈硬化学会総会・学術集会
• [Presentation] Cholesterol efflux capacity (CEC) as a negative predictor of coronary artery disease -From the analysis with newly discovered glycometabolic parameters- (2021)
  • Author(s): Sasaki M, Ezaki H, Ayaori M, Takahiro M, Ochi S, Arakawa J, Suenaga Y, Endo Y, Teramoto M, Sakurada M, Matsuura T, Ikewaki K
  • Organizer: ISA2021
  • Int'l Joint Research
• [Presentation] Impaired HDL Functions and Increased Inflammation in Patients with Sleep Apnea Syndrome (2021)
  • Author(s): Endo Y, Sasaki M, Teramoto M, Arakawa J, Suenaga Y, Ayaori M, Nakayama H, Inoue Y, Ikewaki K
  • Organizer: ISA2021
  • Int'l Joint Research
• [Presentation] Negative (or Unfavorable) Impacts of Ready-made And Dining Out Types Dishes On Metabolic Parameters In Japanese Patients With Dyslipidemia (2021)
  • Author(s): Umezawa A, Maruyama C, Yuri S, Kameyama N, Aisa S, Nishitani A, Ikewaki K, Ayaori M, Waki M, Teramoto T
  • Organizer: ISA2021
  • Int'l Joint Research
• [Presentation] Effects of nutrition education program for the Japan Diet on serum lipids concentrations in patients with dyslipidemia: a randomized controlled trial (2021)
  • Author(s): Maruyama C, Shijo Y, Kameyama N, Umezawa A, Sato A, Nishitani A, Ayaori M, Ikewaki K, Waki M, Teramoto T
  • Organizer: ISA2021
  • Int'l Joint Research
• [Presentation] Lack of association of high-density lipoprotein cholesterol efflux capacity (CEC) with glycometabolic parameters in patients with ischemic heart disease (2021)
  • Author(s): Makoto Sasaki, Hirotaka Ezaki, Makoto Ayaori, Masaki Takahiro, Sae Ochi, Junko Arakawa, Yumiko Suenaga, Yasuhiro Endo, Manami Teramoto, Masami Sakurada, Tomokazu Matsuura, Katsunori Ikewaki
  • Organizer: 第85回日本循環器学会学術集会
• [Presentation] Hepatic NPC2 Overexpression Impairs Reverse Cholesterol Transport by Modulating Production of Bile Acids and HDL Metabolism (2021)
  • Author(s): Junko Arakawa, Makoto Sasaki, Yasuhiro Endo, Manami Teramoto,Yumiko Suenaga, Makoto Ayaori, Katsunori Ikewaki
  • Organizer: 第85回日本循環器学会学術集会
• [Presentation] Patients With Sleep Apnea Syndrome have HDL Dysfunction Which Was Not Rescued By Continuous Positive Airway Pressure (CPAP) Therapy (2021)
  • Author(s): Yasuhiro Endo, Makoto Sasaki, Manami Teramoto, Junko Arakawa,Yumiko Suenaga, Makoto Ayaori, Hideaki Nakayama, Yuichi Inoue, Katsunori Ikewaki
  • Organizer: 第85回日本循環器学会学術集会
• [Presentation] 冠動脈疾患患者におけるコレステロール搬出反応(CEC)と血中アンシポイエチン様因子2(ANGPTL2)濃度 (2020)
  • Author(s): 佐々木誠、江崎裕敬、綾織誠人、政木隆博、越智小枝、三宅隆之、谷脇正哲、荒川純子、末永由美子、遠藤康弘、桜田真己、松浦知和、池脇克則
  • Organizer: 第52回日本動脈硬化学会総会・学術集会
• [Presentation] Sleep Apnea Syndrome Attenuates HDL function (2020)
  • Author(s): Yasuhiro Endo, Makoto Sasaki, Junko Arakawa,Yumiko Suenaga, Hideaki Nakayama, Yuichi Inoue, Katsunori Ikewaki
  • Organizer: 第52回日本動脈硬化学会総会・学術集会
• [Presentation] 肝臓特異的NPC2過剰発現は低HDL血症を惹起しコレステロール逆転送系を抑制する (2020)
  • Author(s): 荒川純子、綾織誠人、佐々木誠、遠藤康弘、末永由美子、寺本麻菜美、池脇克則
  • Organizer: 第52回日本動脈硬化学会総会・学術集会
• [Presentation] 日本食」摂取を推奨する栄養指導がHDL Cholesterol Efflux Capacity(CEC)と血中抗酸化物質及び抗酸化能に及ぼす影響 (2020)
  • Author(s): 梅澤愛理子、丸山千寿子、四條裕里、亀山詞子、佐藤愛紗、遠藤康弘、末永由美子、西谷藍、綾織誠人、脇昌子、寺本民生、池脇克則
  • Organizer: 第52回日本動脈硬化学会総会・学術集会
• [Presentation] 脂質異常症患者における糖・脂質代謝指標に関連する食品群の横断的検討 (2020)
  • Author(s): 亀山詞子、丸山千寿子、四條裕里、梅澤愛理子、佐藤愛紗、綾織誠人、池脇克則、脇昌子、寺本民生
  • Organizer: 第52回日本動脈硬化学会総会・学術集会
• [Presentation] シトステロール血症の治療標的 (2020)
  • Author(s): 池脇克則、佐々木誠、川尻剛照 多田隼人
  • Organizer: 第52回日本動脈硬化学会総会・学術集会